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Updated: Aug 12, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel
Namhee Yu1, Mihwa Hwang1, Youngjoo Lee1
1Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
Background:
A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer.
Methods:
Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles.
Results:
PDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-β expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-β-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939.
Conclusions:
Our PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.
Insights
A novel pharmacogenomic platform using patient-derived cells (PDCs) effectively models lung cancer, identifying resistance mechanisms and potential targeted therapies like XAV939 for advanced or refractory disease.
Area of Science:
- Oncology
- Pharmacogenomics
- Molecular Biology
Background:
- Established a pharmacogenomic platform utilizing patient-derived cells (PDCs) for advanced or refractory lung cancer.
- Aimed to identify resistance mechanisms and guide tailored treatment strategies.
Purpose of the Study:
- To characterize lung cancer PDCs and their genomic similarities to solid tumor tissues.
- To explore drug candidates through integrative analysis of multi-omics data and clinical profiles.
- To identify novel therapeutic targets and treatment strategies for lung cancer.
Main Methods:
- Collected drug sensitivity screening and multi-omics data from 102 lung cancer PDCs.
- Performed integrative analysis correlating genetic variants, gene expression, and clinical profiles.
- Classified PDCs into four molecular subtypes: inflammatory, EMT-like, stemness, and EGFR-dominant.
Main Results:
- PDCs mirrored the genomic characteristics of lung cancer tissues.
- EGFR mutations in the EMT-like subtype correlated with poor response to EGFR-tyrosine kinase inhibitors.
- Alpelisib demonstrated efficacy against SCLC PDCs, inhibiting RB1/TP53 expression and cell growth.
- Osimertinib-resistant PDCs showed upregulated TGF-β and YAP/TAZ, increasing sensitivity to XAV939 (WNT inhibitor).
Conclusions:
- Lung cancer PDCs accurately recapitulate molecular features of the disease.
- Pharmacogenomic analysis of PDCs yields promising therapeutic candidates for lung cancer treatment.
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